We present the 5th data release (DR5) of the Southern Photometric Local Universe Survey (S-PLUS), covering 4592 square degrees across 2491 fields. Observations were conducted with the T80-South, a Brazilian robotic telescope equipped with the Javalambre 12-filter system, containing five broad- and seven narrowband filters. Data products feature FITS images and extensive catalogs containing fluxes, magnitudes, and shape parameters for over 113 million detections. In addition, several value-added catalogs are provided, offering photometric redshifts (photo-zs), object classifications, masks, and extinction coefficients. For the first time, this release includes coverage of 110 square degrees along the Galactic disk, facilitating new research into Galactic structure and stellar populations. The release also provides full coverage of the Hydra Supercluster and numerous other nearby clusters with improved data reduction and calibration, enhancing photo-z accuracy, which is vital for large-scale structure studies. A preliminary analysis of the Hydra and Antlia galaxy clusters up to 5xR200 yields an updated catalog of 1646 cluster members based on both spectroscopic and high-quality photo-zs. Our photometric data shows that both clusters have a similar proportion of galaxies with a Halpha excess relative to their clustercentric distance, though Hydra has a higher fraction near its center. Additionally, the spatial distribution of all objects in our sample highlights a bridge connecting both clusters. We verify that S-PLUS DR5 provides a solid foundation for future scientific investigations, ranging from Solar System studies to Cosmology.